One of the most difficult aspects of treating cocaine dependence is the propensity for relapse to cocaine use after a period of abstinence. While previous research has focused on positive reinforcement and relapse, recent studies have begun to explore the neurobiology of negative reinforcement. Drug use in setting of stress provides negative reinforcement by relieving the stress. Preclinical studies show that kappa receptor activation mediates stress-induced, but not cocaine-induced, cocaine- seeking behavior, suggesting that that kappa receptor activation is selective for negative reinforcement. Previous postmortem studies in cocaine dependence have shown that the kappa receptor is unregulated in this disorder. However, studies investigating the behavioral significance of this change have been lacking due to the inability to image this receptor in vivo. In this application, we will use the newly developed kappa receptor selective PET radiotracer [11C]GR103545 to explore this alteration in neurochemistry in cocaine abuse. In addition, given that dynorphin is known to closely regulate striatal dopamine transmission we use the Monetary Incentive Delay Task, which produces reproducible activation of the striatum, and has been shown to correlate with striatal dopamine transmission. Thus, we will compare alterations neurochemistry and striatal function in cocaine abusers and matched controls for the first time. Additionally, within the cocaine abusing subjects, we will use a laboratory model of stress-induced cocaine seeking behavior in order to explore the correlation between the neurobiology and negative reinforcement. We will also include a group of cocaine abusers who undergo cocaine self-administration sessions following a priming dose of cocaine, in order to demonstrate the specificity of the kappa receptor system for stress-induced cocaine seeking behavior. A final specific aim of this application is to investigate in humans, a well- documented preclinical phenomenon in which binge dosing of cocaine significantly increases dynorphin levels. To investigate this, the cocaine abusing volunteers will participate in binge cocaine self-administrations sessions. Following the sessions, the imaging scans and the stress-induced cocaine self-administration sessions will be repeated, in order to investigate the effect of increased dynorphin in the brain. PUBLIC HEALTH RELEVANCE: The goals of the studies included in this application are to characterize the neurobiology of negative reinforcement in cocaine abuse by focusing on the kappa receptor/dynorphin system in the brain. Using both imaging and behavioral studies, this application seeks to further our understanding this important phenomena in relapse.